AT400437B - Novel N-heterocyclic thienothiazinecarboxamides, process for their preparation and their use - Google Patents
Novel N-heterocyclic thienothiazinecarboxamides, process for their preparation and their use Download PDFInfo
- Publication number
- AT400437B AT400437B AT253093A AT253093A AT400437B AT 400437 B AT400437 B AT 400437B AT 253093 A AT253093 A AT 253093A AT 253093 A AT253093 A AT 253093A AT 400437 B AT400437 B AT 400437B
- Authority
- AT
- Austria
- Prior art keywords
- substituted
- lower alkyl
- aryl
- general formula
- nmr
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 9
- TZIJDLHRFZUDHD-UHFFFAOYSA-N 2h-thieno[2,3-e]thiazine Chemical class C1=CNSC2=C1SC=C2 TZIJDLHRFZUDHD-UHFFFAOYSA-N 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 6- (2-Furyl) -2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic acid Chemical compound 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000013078 crystal Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 238000005481 NMR spectroscopy Methods 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 125000003367 polycyclic group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- IUTILGPEWGLPNB-UHFFFAOYSA-N methyl 5-(furan-2-yl)-3-[(2-methoxy-2-oxoethyl)sulfamoyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=C(S(=O)(=O)NCC(=O)OC)C=C1C1=CC=CO1 IUTILGPEWGLPNB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- JOTKSNHFDPWALG-UHFFFAOYSA-N 6-(furan-2-yl)-4-hydroxy-2-methyl-1,1-dioxo-n-(4-phenyl-1,3-thiazol-2-yl)thieno[2,3-e]thiazine-3-carboxamide Chemical compound OC=1C=2SC(C=3OC=CC=3)=CC=2S(=O)(=O)N(C)C=1C(=O)NC(SC=1)=NC=1C1=CC=CC=C1 JOTKSNHFDPWALG-UHFFFAOYSA-N 0.000 claims 1
- YMTZQPYHMXTCBT-UHFFFAOYSA-N 6-chloro-4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)thieno[2,3-e]thiazine-3-carboxamide Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 YMTZQPYHMXTCBT-UHFFFAOYSA-N 0.000 claims 1
- ZZNVGMGSBMLXBC-UHFFFAOYSA-N 6-chloro-4-hydroxy-2-methyl-1,1-dioxo-n-(4-phenyl-1,3-thiazol-2-yl)thieno[2,3-e]thiazine-3-carboxamide Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC(SC=1)=NC=1C1=CC=CC=C1 ZZNVGMGSBMLXBC-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
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- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 4
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
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- 238000009835 boiling Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- PYSJLPAOBIGQPK-UHFFFAOYSA-N 4-phenyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC=CC=2)=C1 PYSJLPAOBIGQPK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
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- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- AEBDXDMSPHONIJ-UHFFFAOYSA-N methyl 3-chlorosulfonyl-5-(furan-2-yl)thiophene-2-carboxylate Chemical compound ClS(=O)(=O)C1=C(C(=O)OC)SC(C=2OC=CC=2)=C1 AEBDXDMSPHONIJ-UHFFFAOYSA-N 0.000 description 2
- HITUAYIBHWKKFU-UHFFFAOYSA-N methyl 6-chloro-4-hydroxy-2-methyl-1,1-dioxothieno[2,3-e]thiazine-3-carboxylate Chemical compound O=S1(=O)N(C)C(C(=O)OC)=C(O)C2=C1C=C(Cl)S2 HITUAYIBHWKKFU-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
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- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
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- UKMUVYNLIFHONL-UHFFFAOYSA-N 6-chloro-2-methyl-1,1-dioxo-n-pyridin-2-ylthieno[2,3-e]thiazine-3-carboxamide Chemical compound C=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 UKMUVYNLIFHONL-UHFFFAOYSA-N 0.000 description 1
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- 201000004624 Dermatitis Diseases 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
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- 229920000084 Gum arabic Polymers 0.000 description 1
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- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
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- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HSNUIYJWTSJUMS-UHFFFAOYSA-N sodium;trimethyl(oxido)silane Chemical compound [Na+].C[Si](C)(C)[O-] HSNUIYJWTSJUMS-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
AT 400 437 BAT 400 437 B
Die Erfindung betrifft neue Thienothiazinderivate, ein Verfahren zu ihrer Herstellung und ihre Verwendung.The invention relates to new thienothiazine derivatives, a process for their preparation and their use.
Aus US 4,180,662 sind Thienothiazinderivate bekannt, die durch einen unsubstituierten Pyridinkern substituiert sind. Diese Verbindungen weisen gute Cyciooxygenasehemmung auf.No. 4,180,662 discloses thienothiazine derivatives which are substituted by an unsubstituted pyridine nucleus. These compounds have good cyciooxygenase inhibition.
Ferner sind aus Chemical Abstracts, Band 111, Nr.19, 166771η und Chemical Abstracts, Band 115, Nr. 3, 21532h Thienothiazinderivate bekannt, die am Pyridinkern unsubstituiert, oder durch eine Hydroxylgruppe substituiert sind. Auch diese Verbindungen weisen eine gute Cyciooxygenasehemmung auf.Furthermore, from Chemical Abstracts, Volume 111, No. 19, 166771η and Chemical Abstracts, Volume 115, No. 3, 21532h thienothiazine derivatives are known which are unsubstituted on the pyridine nucleus or substituted by a hydroxyl group. These compounds also have good cyciooxygenase inhibition.
Es konnten nun neue, durch einen substituierten Fünfring substituierte Thienothiazinderivate gefunden werden, die bei weitgehender Beibehaltung der Cyciooxygenasehemmung eine signifikant erhöhte Hemmung der 5-Lipoxygenase bewirken.It has now been possible to find new thienothiazine derivatives which are substituted by a substituted five-membered ring and which, with the cyciooxygenase inhibition largely retained, bring about a significantly increased inhibition of the 5-lipoxygenase.
Gegenstand der Erfindung sind demnach neue, therapeutisch wertvolle Thienothiazin-Derivate der allgemeinen FormelThe invention accordingly relates to new, therapeutically valuable thienothiazine derivatives of the general formula
worin A Halogen oder einen mono- oder polycyclischen 5-12 gliedrigen, gegebenenfalls teilweise hydrierten Aryl- oder Heteroarylrest mit 1-4 Heteroatomen wie 0, S und N, der gegebenenfalls mit Niederalkyl, Perfluorniederalkyl, Aryl, Heteroaryl, substituiertem Aryl, substituiertem Heteroaryl, Halogen, Niederaikoxy, Aryloxy, substituiertem Aryloxy, Heteroaryioxy, substituiertem Heteroaryloxy und Nitro substituiert sein kann, in denen die angesprochenen Substituenten in dem substituierten Aryl, substituierten Heteroaryl, substituierten Aryloxy und substituierten Heteroaryloxy Halogen, Niederalkyl, Perfluorniederalkyl oder Niederaikoxy bedeuten; M eine Einfachbindung, eine geradkettige oder verzweigte Kohienstoffkette mit. 1-12 Kohlenstoffatomen in der Kette, wobei diese Kette ein oder mehrere Doppel- und/oder Dreifachbindungen und/oder ein oder mehrere Heteroatome, wie 0, S und N, enthalten kann, einen 5-12 gliedrigen mono- oder polycyclischen gegebenenfalls teilweise hydrierten Aryl- oder Heteroarylrest, der durch Halogen, Niederalkyl oder Niederaikoxy substituiert sein kann; Q eine Einfachbindung oder ein Heteroatom wie 0, S und N; R Wasserstoff, einen 5-12 gliedrigen mono- oder polycyclischen Aryl- oder Heteroarylrest mit 1-4 Heteroatomen wie 0, S und N, der gegebenenfalls teilweise hydriert sein kann, oder auch ein oder mehrfach mit Halogen, Niederalkyl oder Niederaikoxy substituiert sein kann;wherein A is halogen or a mono- or polycyclic 5-12-membered, optionally partially hydrogenated aryl or heteroaryl radical with 1-4 heteroatoms such as 0, S and N, optionally substituted with lower alkyl, perfluoro-lower alkyl, aryl, heteroaryl, substituted aryl, heteroaryl, Halogen, lower aikoxy, aryloxy, substituted aryloxy, heteroaryioxy, substituted heteroaryloxy and nitro may be substituted, in which the substituents mentioned in the substituted aryl, substituted heteroaryl, substituted aryloxy and substituted heteroaryloxy mean halogen, lower alkyl, perfluoro-lower alkyl or lower aikoxy; M a single bond, a straight-chain or branched carbon chain. 1-12 carbon atoms in the chain, which chain may contain one or more double and / or triple bonds and / or one or more heteroatoms, such as 0, S and N, a 5-12-membered mono- or polycyclic optionally partially hydrogenated Aryl or heteroaryl radical which can be substituted by halogen, lower alkyl or lower alkoxy; Q is a single bond or a heteroatom such as 0, S and N; R is hydrogen, a 5-12-membered mono- or polycyclic aryl or heteroaryl radical with 1-4 heteroatoms such as 0, S and N, which can optionally be partially hydrogenated, or can be substituted one or more times with halogen, lower alkyl or lower alkoxy;
Ri Wasserstoff, oder R, 0Ri is hydrogen, or R, 0
X O^R, worin R2 Niederalkyl und R3 Niederalkyl, Aryl oder -ORt mit R4. Niederalkyl, Cycloalkyl mit 4-8 Kohlenstoffatomen oder Aryl; X und Y unabhängig voneinander CH, NRg, 0 oder S, mit R6 Wasserstoff oder Niederalkyl, bedeuten, sowie ihre pharmazeutisch verwendbaren Salze.X O ^ R, wherein R2 is lower alkyl and R3 is lower alkyl, aryl or -ORt with R4. Lower alkyl, cycloalkyl of 4-8 carbon atoms or aryl; X and Y are independently CH, NRg, 0 or S, with R6 hydrogen or lower alkyl, and their pharmaceutically usable salts.
Ein weiterer Gegenstand der vorliegenden Verbindung ist ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I), welches dadurch gekennzeichnet ist, daß man eine Verbindung der allgemeinen Formel 2The present invention further relates to a process for the preparation of compounds of the general formula (I), which is characterized in that a compound of the general formula 2
AT 400 437 BAT 400 437 B
worin Ri Wasserstoff, Rs Niederalkyl bedeutet und A obige Bedeutung hat, mit einer Verbindung der allgemeinen Formel Η,Ν x-y umsetzt, wobei X, Y, M, Q und R obige Bedeutung haben, und die so erhaltenen Verbindungen der allgemeinen Formel (I) für Ri = Wasserstoff gegebenenfalls in ihre pharmazeutisch verwendbaren Salze überführt oder mit einer Verbindung der allgemeinen Formelin which Ri is hydrogen, Rs is lower alkyl and A has the meaning given above, with a compound of the general formula Η, Ν xy, where X, Y, M, Q and R have the meaning given above, and the compounds of the general formula (I) thus obtained for Ri = hydrogen optionally converted into their pharmaceutically usable salts or with a compound of the general formula
ZZ.
(IV), worin Z Chlor oder Brom bedeutet und Rz und R3 obige Bedeutung haben, zu den Verbindungen der allgemeinen Formel (!) mit Ri nicht Wasserstoff umsetzt.(IV), in which Z is chlorine or bromine and Rz and R3 have the above meaning, does not react with R i to give the compounds of the general formula (!).
Der oben verwendete Ausdruck "Aryl” kann beispielsweise Phenyl, Naphthyl, u.ä. und der Ausdruck "Heteroaryi" kann bespielsweise Thienyl, Furyi, Pyrrolyl, Pyridinyl, Pyrimidinyl, Pyridazinyl, Imidazolyl, Pyrazolyl, Thiazolyl, Oxazolyl, Oxadiazolyl, Thiadiazolyl, Pyranyl, Thiopyranyl, Benzo[b]furyl, Benzo[b]-thienyl, Chinolinyl, iso-Chinolinyl und dergleichen bedeuten.The term "aryl" used above can be, for example, phenyl, naphthyl, and the like. and the expression " heteroaryi " For example, thienyl, furyi, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyranyl, thiopyranyl, benzo [b] furyl, benzo [b] -thienyl, quinolinyl and iso mean.
Der oben verwendete Ausdruck "Halogen" bedeutet Fluor, Chlor, Brom oder lod. Der oben verwendete Ausdruck "Niederalkyl" bedeutet einen geradkettigen oder verzweigten Alkylrest mit 1-4 Kohienstoffatomen, beispielsweise Methyl, Ethyl, n- und i-Propyl, n-, i- und t-Butyl.The term " halogen " means fluorine, chlorine, bromine or iodine. The term " lower alkyl " means a straight-chain or branched alkyl radical having 1-4 carbon atoms, for example methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
Der oben verwendete Ausdruck "Niederalkyloxy" bedeutet einen geradkettigen oder verzweigten Alkoxyrest mit 1-4 Kohlenstoffatomen, beispielsweise Methoxy, Ethoxy, n- und i-Propoxy, n-, i- und t-Butoxy.The term " lower alkyloxy " means a straight-chain or branched alkoxy radical having 1-4 carbon atoms, for example methoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy.
Die erfindungsgemäßen Umsetzungen werden am besten so durchgeführt, daß man entweder A) die Verbindung der allgemeinen Formel (II) in einem inerten Lösungsmittel, wie Diethylether, THF, Dioxan, Toluoi, Benzol usw., löst und bei einer Temperatur zwischen -20 *C und 1 00 °C ein Äquivalent einer starken Base, wie Butyllithium oder LDA, zusetzt, zu dieser Salzlösung 1-10 Äquivalente einer Verbindung der allgemeinen Formel (III) zusetzt, mindestens ein weiteres Äquivalent der starken Base zusetzt und zwischen 0,5 und 60 Stunden bei -20 "C bis 100°C rührt, oder B) eine Lösung der Verbindungen (II) und (III) in einem inerten, hochsiedenden Lösungsmittel, wie Toluol, Xylol, Pyridin, Chinolin, DMF, DMSO oder HMPA usw., 1-30 Stunden zwischen 100 ’C und 200 * C erhitzt, die so erhaltenen Verbindungen der allgemeinen Formel (I) werden für den Fall Ri nicht Wasserstoff entweder C) in einem inerten Lösungsmittel, wie Aceton, DMF, DMSO oder HMPA mit mindestens einem Äquivalent einer Base, wie NaH, Natriumtrimethylsilanolat u.ä., bei Raumtemperatur umgesetzt und 1-100 Stunden bei 0-150 *C mit mindestens einem Äquivalent einer Verbindung der allgemeinen Formel (IV) gerührt oder D) in einem basischen Lösungsmittel wie Triethylamin, Pyridin, Chinolin u.ä., mit mindestens einem Äquivalent einer Verbindung der allgemeinen Formel (IV) 1-100 Stunden bei 0-150 ° C gerührt.The reactions according to the invention are best carried out by either A) dissolving the compound of the general formula (II) in an inert solvent, such as diethyl ether, THF, dioxane, toluene, benzene, etc., and at a temperature between -20 ° C. and 100 ° C. adds one equivalent of a strong base, such as butyllithium or LDA, adds 1-10 equivalents of a compound of the general formula (III) to this salt solution, adds at least one further equivalent of the strong base and between 0.5 and 60 Stirring hours at -20 " C to 100 ° C, or B) a solution of the compounds (II) and (III) in an inert, high-boiling solvent such as toluene, xylene, pyridine, quinoline, DMF, DMSO or HMPA etc. , 1-30 hours heated between 100 'C and 200 * C, the compounds of the general formula (I) thus obtained are not hydrogen or C in the case of Ri in an inert solvent such as acetone, DMF, DMSO or HMPA with at least an equivalent t a base such as NaH, sodium trimethylsilanolate and the like, reacted at room temperature and stirred for 1-100 hours at 0-150 * C with at least one equivalent of a compound of the general formula (IV) or D) in a basic solvent such as triethylamine, Pyridine, quinoline and the like, stirred with at least one equivalent of a compound of general formula (IV) for 1-100 hours at 0-150 ° C.
Die bei dieser Umsetzung erhaltenen Verbindungen der allgemeinen Formel (I) mit Ri = Wasserstoff sind saure Verbindungen und können auf übliche Weise mit anorganischen oder organischen Basen in ihre 3The compounds of the general formula (I) with R 1 = hydrogen obtained in this reaction are acidic compounds and can be used in the usual manner with inorganic or organic bases in their 3rd
AT 400 437 B pharmazeutisch verträglichen Salze überführt werden.AT 400 437 B pharmaceutically acceptable salts are transferred.
Die Salzbildung kann beispielsweise durchgeführt werden, indem man die Verbindungen der Formel (I) in einem geeigneten Lösungsmittel, z.B. Wasser, einem niederen aliphatischen Alkohol, THF, Dioxan, Benzol, Diethylether, DMF oder DMSO löst, eine äquivalente Menge der gewünschten Base zusetzt, für eine gute Durchmischung sorgt und nach beendeter Salzbildung das Lösungsmittel im Vakuum abzieht. Gegebenenfalls können die Salze nach der Isolierung umkristallisiert werden.Salt formation can be carried out, for example, by the compounds of formula (I) in a suitable solvent, e.g. Dissolves water, a lower aliphatic alcohol, THF, dioxane, benzene, diethyl ether, DMF or DMSO, adds an equivalent amount of the desired base, ensures thorough mixing and removes the solvent in vacuo after the salt formation has ended. If necessary, the salts can be recrystallized after isolation.
Pharmazeutisch verwendbare Salze sind z.B. Metallsalze, insbesondere Alkalimetall- und Erdalkalimetallsalze, wie Natrium-, Kalium-, Magnesium- oder Calciumsalze. Andere pharmazeutische Salze sind beispielsweise leicht kristallisierende Ammoniumsalze. Letztere leiten sich ab von Ammoniak oder von organischen Aminen, z.B. Mono-, Di- oder Tri-nieder-(alkyl, cycloalkyl oder hydroxyalkyl)-aminen, Niederalkylendiaminen oder (Hydroxy-niederalkyl oder Aryl-niederalkyl)-niederalkylammoniumbasen, z.B. Methylamin, Diethylamin, Triethylamin, Dicyclohexylamin, Triethanolamin, Ethylendiamin, Tris(hydroxymethyl)-ami-nomethan, Benzyltrimethylammoniumhydroxid und dergleichen.Pharmaceutically acceptable salts are e.g. Metal salts, especially alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts. Other pharmaceutical salts are, for example, easily crystallizing ammonium salts. The latter are derived from ammonia or from organic amines, e.g. Mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylene diamines or (hydroxy-lower alkyl or aryl-lower alkyl) lower alkylammonium bases, e.g. Methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane, benzyltrimethylammonium hydroxide and the like.
Die Verbindungen der allgemeinen Formel (II), (III) und (IV) sind literaturbekannt oder können analog dazu nach üblichen und dem Fachmann geläufigen Methoden hergestellt werden.The compounds of the general formulas (II), (III) and (IV) are known from the literature or can be prepared analogously thereto by customary methods which are familiar to the person skilled in the art.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) und deren Salze sind oral wirksam und zeigen im Vergleich zu 6-Chlor-2-methyl-N-(2-pyridyl)-2H-thieno[2,3-e]-1,2-thiazin-3-carbonsäureamid- 1.1- dioxid ("LORNOXICAM", US-Patent 4,180,662) überraschender Weise eine signifikant erhöhte Hemmung der 5-Lipoxygenase bei weitgehendster Beibehaltung der Cyclooxygenasehemmung.The compounds of the general formula (I) and their salts according to the invention are orally active and, in comparison to 6-chloro-2-methyl-N- (2-pyridyl) -2H-thieno [2,3-e] -1,2 -thiazine-3-carboxamide 1.1- dioxide (" LORNOXICAM ", US Pat. No. 4,180,662) surprisingly shows a significantly increased inhibition of 5-lipoxygenase while largely maintaining the cyclooxygenase inhibition.
Sie sind daher zur Behandlung von Beschwerden die durch das natürliche Produkt der 5-Lipoxygenase nämlich dem Leucotrien-B* und den Cyclooxygenaseprodukten mitverursacht werden, wie z.B. Entzündung und Schmerz bei allergischem Asthma, Arthritis, Hautallergie, rheumatische Beschwerden usw., besonders gut geeignet.They are therefore used to treat symptoms caused by the natural product of 5-lipoxygenase, namely leucotriene-B * and cyclooxygenase products, such as Inflammation and pain in allergic asthma, arthritis, skin allergy, rheumatic complaints etc., particularly well suited.
Aufgrund dieser pharmakologischen Eigenschaften können die neuen Verbindungen allein oder in Mischung mit anderen Wirksubstanzen in Form üblicher galenischer Zubereitungen als Heilmittel zur Behandlung von Erkrankungen, die durch Hemmung der 5-Lipoxygenase und der Cyclooxygenase geheilt oder gelindert werden, Verwendung finden.Because of these pharmacological properties, the new compounds can be used alone or in a mixture with other active substances in the form of conventional pharmaceutical preparations as medicaments for the treatment of diseases which are cured or alleviated by inhibition of 5-lipoxygenase and cyclooxygenase.
Die Erfindung bezieht sich weiterhin auf Heilmittel, die z.B. in Form pharmazeutischer Präparate Verwendung finden, welche die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) und ihre Salze in Mischung mit einem für die orale, enterale, parenterale und topicale Applikation geeigneten, pharmazeutischen, organischen oder anorganischen Trägermaterial, beispielsweise Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole, Vaseline oder dergleichen enthalten.The invention further relates to remedies which e.g. in the form of pharmaceutical preparations which contain the compounds of the general formula (I) and their salts according to the invention in a mixture with a pharmaceutical, organic or inorganic carrier material suitable for oral, enteral, parenteral and topical application, for example water, gelatin, gum arabic , Milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly or the like.
Die pharmazeutischen Präparate können in fester Form z.B. als Tabletten, Filmtabletten, Dragees, Suppositorien, Kapseln, Mikrokapseln oder in flüssiger Form z.B. als Lösungen, Injektionslösungen, Suspensionen oder Emulsionen oder in Zusammensetzungen mit verzögerter Freigabe des Wirkstoffes vorliegen. Gegebenfalls sind sie sterilisiert und/oder enthalten Hiifsstoffe, wie Konservierungs-, Stabiiisierungs- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer.The pharmaceutical preparations can be in solid form e.g. as tablets, film-coated tablets, dragees, suppositories, capsules, microcapsules or in liquid form e.g. as solutions, solutions for injection, suspensions or emulsions or in compositions with delayed release of the active ingredient. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers or emulsifiers, salts for changing the osmotic pressure or buffers.
Insbesondere können pharmazeutische Präparate die erfindungsgemäßen Verbindungen in Kombination mit anderen therapeutisch wertvollen Stoffen enthalten. Mit diesen können die erfindungsgemäßen Verbindungen zusammen mit den oben angegebenen Hilfs- und/oder Trägerstoffen zu Kombinationspräparaten formuliert werden.In particular, pharmaceutical preparations can contain the compounds according to the invention in combination with other therapeutically valuable substances. These can be used to formulate the compounds according to the invention together with the auxiliaries and / or excipients specified above to give combination preparations.
Die neuen Verbindungen können in den erfindungsgemäßen pharmazeutischen Zusammensetzungen in einem Anteil von etwa 4-200 mg pro Tablette vorhanden sein, wobei der Rest ein pharmazeutisch annehmbarer Füllstoff ist.The new compounds can be present in the pharmaceutical compositions according to the invention in a proportion of approximately 4-200 mg per tablet, the rest being a pharmaceutically acceptable filler.
Eine geeignete Dosis zur Verabreichung der neuen Verbindungen beträgt etwa 1-200 mg/kg pro Tag, jedoch kommen, je nach dem Zustand des zu behandelnden Patienten, auch andere Dosen in Frage. Die neuen Verbindungen könn:~ in mehreren Dosen und auf oralem Weg verabreicht werden.A suitable dose for the administration of the new compounds is about 1-200 mg / kg per day, but other doses are also possible, depending on the condition of the patient to be treated. The new compounds can be: ~ administered in multiple doses and orally.
Die folgenden Beispiele erläutern die Erfindung näher, ohne das diese darauf beschränkt sein soll:The following examples explain the invention in more detail, without any intention that it should be restricted thereto:
Beispiel 1 6-Chlor-4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e3-1,2-thiazin-3-carboxamid-1,1-dioxid 1.32g (4.25 mMol) 6-Chlor-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazin-3-carbonsäuremethylester- 1.1- dioxid und 0.47g (4.30 mMol) 2-Thiazolamin werden in 12 ml Xylol abs. 17.5 Std. zum Sieden erhitzt. Nach Abziehen des Lösungsmittels wird das Rohprodukt mit 5x20 ml eiskaltem Diethylether digeriert, in 1N NaOH-Lösung aufgenommen, mit Aktivkohle heiß filtriert, angesäuert und der Niederschlag abfiltriert und 4Example 1 6-Chloro-4-hydroxy-2-methyl-N- (2-thiazolyl) -2H-thieno [2,3-e3-1,2-thiazine-3-carboxamide-1,1-dioxide 1.32g ( 4.25 mmol) 6-chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic acid methyl ester-1.1-dioxide and 0.47 g (4.30 mmol) 2-thiazolamine in 12 ml abs. Heated to boiling for 17.5 hours. After the solvent has been stripped off, the crude product is digested with 5 × 20 ml of ice-cold diethyl ether, taken up in 1N NaOH solution, filtered hot with activated carbon, acidified and the precipitate is filtered off and 4
AT 400 437 B getrocknet.AT 400 437 B dried.
Ausbeute: 0.175g gelbe Kristalle (10.94 % d.Th.)Yield: 0.175g yellow crystals (10.94% of theory)
Fp: 223-225 °C (H20) DC: Bz/Dx/MeOH 10:1:1 Rf: 0.68 1H-NMR: (DMSO-d6) δ (ppm) = 7.66 (s; 1H, Thio-H7); 7,60 (d, 1H, Thaz-H5); 7.22 (d: 1H, Thaz-H4); 2.96 (s; 3H, N-CH3) 13C-NMR: (DMSO-de) δ (ppm) = 166.09; 164.78; 156.45:138.41; 136.91; 135.23; 127.29; 123.00; 112.95; 111.92; 38.82 Beispiel 2 6-Chlor-4-hydroxy-2-methyl-N-(4-phenyl-2-thiazolyl)-2H-thieno-[2,3-e3-1,2-thiazin-3-carboxamid-1,1- dioxid 1.37g (4.417 mMol) 6-Chior-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazin-3-carbonsäure-methylester- 1.1- dioxid und 0.78g (4.426 mMol) 4-Phenyl-2-thiazolamin werden in 12.6 ml Xylol abs. zum Sieden erhitzt. Nach 3.5 Std. und 5.5 Std. werden jeweils 0.4g (2.269 mMol) 4-Phenyl-2-thiazolamin zugesetzt. Nach 6 Std wird das LM abgezogen. Das Rohprodukt wird mit 3x20ml eiskaltem Diethylether digeriert, mit heißem Ethylaikohoi gewaschen und aus Methylenchlorid/Aktivkohle umkristal-lisiert.Mp: 223-225 ° C (H20) TLC: Bz / Dx / MeOH 10: 1: 1 Rf: 0.68 1H-NMR: (DMSO-d6) δ (ppm) = 7.66 (s; 1H, Thio-H7); 7.60 (d, 1H, Thaz-H5); 7.22 (d: 1H, Thaz-H4); 2.96 (s; 3H, N-CH3) 13C-NMR: (DMSO-de) δ (ppm) = 166.09; 164.78; 156.45: 138.41; 136.91; 135.23; 127.29; 123.00; 112.95; 111.92; 38.82 Example 2 6-chloro-4-hydroxy-2-methyl-N- (4-phenyl-2-thiazolyl) -2H-thieno- [2,3-e3-1,2-thiazine-3-carboxamide-1, 1-dioxide 1.37g (4,417 mmol) 6-chloro-4-hydroxy-2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 0.78g (4,426 mmol) 4-phenyl-2-thiazolamine are abs in 12.6 ml of xylene. heated to boiling. After 3.5 hours and 5.5 hours, 0.4 g (2,269 mmol) of 4-phenyl-2-thiazolamine are added in each case. The LM is removed after 6 hours. The crude product is digested with 3x20ml ice-cold diethyl ether, washed with hot ethyl alcohol and recrystallized from methylene chloride / activated carbon.
Ausbeute: 1.15g gelbe Kristalle (57.5 % d.Th.)Yield: 1.15 g of yellow crystals (57.5% of theory)
Fp: 241-244 °C (CH2CI2) DC: CH2CI2/MeOH 40:1 Rf: 0.30 ’H-NMR: (DMSO-ds) δ (ppm) = 7.88 (d; 2H, Ph-H2,6); 7.68 (s; 1H, Thio-H7); 7.60 (s; 1H, Thiaz-H5); 7,54-7,33 (m; 3H, Ph-H3,4,5); 2.94 (s; 3H, N-CH3) ,3C-NMR: (DMSO-de) δ (ppm)· 165.58; 161.93; 155.16; 142.72; 136.93; 136.39; 135.50; 131.11; 128.84; 128.66; 125.77; 122.77; 111.11; 108.08; 38.78Mp: 241-244 ° C (CH2CI2) DC: CH2CI2 / MeOH 40: 1 Rf: 0.30 ’H-NMR: (DMSO-ds) δ (ppm) = 7.88 (d; 2H, Ph-H2.6); 7.68 (s; 1H, thio-H7); 7.60 (s; 1H, thiaz-H5); 7.54-7.33 (m; 3H, Ph-H3.4.5); 2.94 (s; 3H, N-CH3), 3C-NMR: (DMSO-de) δ (ppm) x 165.58; 161.93; 155.16; 142.72; 136.93; 136.39; 135.50; 131.11; 128.84; 128.66; 125.77; 122.77; 111.11; 108.08; 38.78
Beispiel 3 6-(2-Furyl)-4-hydroxy-2-methvl-N-(4-phenvl-2-thiazoiyl)-2H-thieno-[2,3-eI-1,2-thiazin-3-carboxamid- 1.1- dioxid 0.49g (1.459 mMol) 6-(2-Furyl)-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazin-3-carbonsäure-methyle-ster-l,1-dioxid und 0.77g (4.386 mMol) 4-Phenyl-2-thiazolamin werden in 5 ml Xylol abs. 6 Std. zum Sieden erhitzt. Nach Abziehen des Lösungs-mittels wird das Rohprodukt mit 3x10 ml eiskaltem Ethanol digeriert und aus Dichlormethan/Aktivkohle umkristallisiert.Example 3 6- (2-Furyl) -4-hydroxy-2-methylene-N- (4-phenylene-2-thiazoiyl) -2H-thieno [2,3-eI-1,2-thiazine-3-carboxamide - 1.1- dioxide 0.49g (1.459 mmol) 6- (2-furyl) -4-hydroxy-2-methyl-2H-thieno- [2,3-e] -1,2-thiazine-3-carboxylic acid methyl- ster-l, 1-dioxide and 0.77g (4,386 mmol) 4-phenyl-2-thiazolamine are abs. in 5 ml xylene. Heated to boiling for 6 hours. After the solvent has been stripped off, the crude product is digested with 3x10 ml of ice-cold ethanol and recrystallized from dichloromethane / activated carbon.
Ausbeute: 0.34g gelbe Kristalle (48.0 % d.Th.)Yield: 0.34 g of yellow crystals (48.0% of theory)
Fp: ab 240°C Zers. (CH2CI2) DC: CH2CI2/MeOH 50:1 Rf: 0.23 Bz/Dx/MeOH 10:1:1 Rf: 0.71 ’H-NMR: (DMSO-de) δ (ppm) = 7,93-7.81 (m, 4H, Thio-H7, Ph-H2,6, Fu-H5); 7,64 (s, 1H, Thaz-H5); 7,53-7,31 (m, 3H, Ph-H3,4,5); 7,22 (d, 1H, Fu-H3); 6,71 (dd, 1H, Fu-H4); 2.98 (s; 3H, N-CH3) 13C-NMR: (DMSO-ds) δ (ppm) =165.71; 161.26; 155.92; 146.93; 144.46; 143.85; 138.62; 138.52; 134.60; 131.82; 128.84; 128.48; 125.77; 117.53; 112.90; 110.77; 109.42; 108.10; 38.93 Das Ausgangsmaterial kann wie folgt hergestelit werden: 4-Methyibenzolsulfonsäure, [2-cyano-1 -(2-furyl)ethenyl]-esterMp: from 240 ° C dec. (CH2CI2) TLC: CH2CI2 / MeOH 50: 1 Rf: 0.23 Bz / Dx / MeOH 10: 1: 1 Rf: 0.71 'H NMR: (DMSO-de) δ (ppm) = 7.93-7.81 (m, 4H, Thio-H7, Ph-H2.6, Fu-H5); 7.64 (s, 1H, Thaz-H5); 7.53-7.31 (m, 3H, Ph-H3,4,5); 7.22 (d, 1H, Fu-H3); 6.71 (dd, 1H, Fu-H4); 2.98 (s; 3H, N-CH3) 13C-NMR: (DMSO-ds) δ (ppm) = 165.71; 161.26; 155.92; 146.93; 144.46; 143.85; 138.62; 138.52; 134.60; 131.82; 128.84; 128.48; 125.77; 117.53; 112.90; 110.77; 109.42; 108.10; 38.93 The starting material can be prepared as follows: 4-methylbenzenesulfonic acid, [2-cyano-1 - (2-furyl) ethenyl] ester
Zu 45.75 g (339 mMol) b-Oxo-2-furanpropannitril und 47.95 g (474 mMol) N-Methylmorpholin in 100 ml absolutem Dichlormethan werden bei -5 bis 0°C 67.78 g (356 mMol) p-Toluolsulfonsäurechlorid in 100 ml absolutem Dichlormethan getropft und eine Stunde nachgerührt.To 45.75 g (339 mmol) of b-oxo-2-furanpropanitrile and 47.95 g (474 mmol) of N-methylmorpholine in 100 ml of absolute dichloromethane, 67.78 g (356 mmol) of p-toluenesulfonic acid chloride in 100 ml of absolute are obtained at -5 to 0 ° C Dropped dichloromethane and stirred for an hour.
Das Lösungsmittel wird abgezogen, der Rückstand zwischen 500 ml Essigsäureethylester und 400 ml 1n Salzsäure verteilt und die wäßrige Phase mit 6x150 ml Essigsäureethylester extrahiert. Die vereinten Extrakte werden über NaiSCL/Aktivkohle getrocknet, filtriert und das Extraktionsmittel abdestilliert. Den 5 ΑΤ 400 437 Β erhaltenen Feststoff kristallisiert man aus 150 ml Toluol/Aktivkohle um.The solvent is drawn off, the residue is partitioned between 500 ml of ethyl acetate and 400 ml of 1N hydrochloric acid and the aqueous phase is extracted with 6 × 150 ml of ethyl acetate. The combined extracts are dried over NaiSCL / activated carbon, filtered and the extractant is distilled off. The 5 ΑΤ 400 437 Β solid obtained is recrystallized from 150 ml of toluene / activated carbon.
Ausbeute: 92.48 g farblose Kristalle (94% d.Th.) DC: LM—Bz-.EhO - 10:1; 0.65 Fp.: 109-111 *C (Toluol) ^-NMR: (DMSO-ds) d(ppm): 8.00-7.85 (m, 3H, Bz-H2,6, Fu-H5); 7.60-7.48 (m, 2H, Bz-H3,5) 6.74 (dd, 1H, Fu-H3’); 6.57 (dd, 1H, Fu-H4*); 6.33 (s, 1H, CH-CN); 2.45 (s, 3H, CH3) 13C-NMR: (DMSO-ds) d(ppm): 150.2; 147.7; 146.8; 145.4; 131.1; 130.4; 128.4; 115.9; 114.4; 113.1; 87.3; 21.2 3-Amino-5-(2-furyl)-2-thiophencarbonsäuremethylester Hydrochlorid 16.75 g (309 mMol) Natriummethanolat in 750 ml absolutem Methanol werden bei 15-20'C mit 32.75 g (309 mMol) Thioglycolsäuremethylester versetzt und 20 Minuten bei Raumtemperatur gerührt. Anschließend gibt man in einer Portion 74.38 g (257 mMol) 4-Methylbenzolsulfonsäure-[2-cyano-l-(2-furyl)ethenyl]-ester zu und rührt weitere 2\ Stunden.Yield: 92.48 g of colorless crystals (94% of theory) TLC: LM — Bz-.EhO - 10: 1; 0.65 mp: 109-111 * C (toluene) ^ -NMR: (DMSO-ds) d (ppm): 8.00-7.85 (m, 3H, Bz-H2.6, Fu-H5); 7.60-7.48 (m, 2H, Bz-H3.5) 6.74 (dd, 1H, Fu-H3 '); 6.57 (dd, 1H, Fu-H4 *); 6.33 (s, 1H, CH-CN); 2.45 (s, 3H, CH3) 13C-NMR: (DMSO-ds) d (ppm): 150.2; 147.7; 146.8; 145.4; 131.1; 130.4; 128.4; 115.9; 114.4; 113.1; 87.3; 21.2 3-Amino-5- (2-furyl) -2-thiophenecarboxylic acid methyl ester, hydrochloride 16.75 g (309 mmol) of sodium methoxide in 750 ml of absolute methanol are mixed with 32.75 g (309 mmol) of methyl thioglycolate at 15-20'C and 20 minutes at room temperature touched. Then 74.38 g (257 mmol) of 4-methylbenzenesulfonic acid [2-cyano-l- (2-furyl) ethenyl] ester are added in one portion and the mixture is stirred for a further 2 hours.
Nach dem Abziehen des Lösungsmittels wird zwischen 500 ml Wasser und 400 ml Diethylether verteilt, noch einmal mit 200 ml Diethylether extrahiert und die organische Phase über Na2SOi/Aktivkohle getrocknet, filtriert und auf 400 ml eingeengt. Nun leitet man unter Eiskühlung und kräftiger Rührung eine Stunde trockenen Chlorwasserstoff ein, kühlt auf -20 *C, filtriert das ausgefallene Hydrochlorid ab und digeriert mit 2x100 ml trockenem Diethylether.After the solvent has been stripped off, it is partitioned between 500 ml of water and 400 ml of diethyl ether, extracted again with 200 ml of diethyl ether and the organic phase is dried over Na2SOi / activated carbon, filtered and concentrated to 400 ml. Now, with ice cooling and vigorous stirring, dry hydrogen chloride is introduced for one hour, cooled to -20 * C, the precipitated hydrochloride is filtered off and digested with 2x100 ml of dry diethyl ether.
Ausbeute: 37.74 g farblose Kristalle (57% d.Th.) DC (Amin): LM...BziEtzO = 5:1; 0.4 Fp.: 134-136 °C (Ether) 1H-NMR: (DMSO-ds) d(ppm): 7.79 (dd, 1H, Fu-H5); 7.46 (sbrei„ 3H, NHgCI); 6.90 (dd, 1H, Fu-H3); 6.87 (s, 1H, Th-H4); 6.62 (dd, 1H, Fu-H4); 3.72 (s, 3H, CH3) 13C-NMR: (DMSO-ds) d(ppm): 164.0; 154.2; 148.0; 144.1; 136.9, 115.3; 112.7; 108.6; 97.5, 51.3 3-Chlorsulfonyl-5-(2-furyl)-2-thiophencarbonsäuremethylesterYield: 37.74 g of colorless crystals (57% of theory) TLC (amine): LM ... BziEtzO = 5: 1; 0.4 mp: 134-136 ° C (ether) 1H NMR: (DMSO-ds) d (ppm): 7.79 (dd, 1H, Fu-H5); 7.46 (slurry "3H, NHgCI); 6.90 (dd, 1H, Fu-H3); 6.87 (s, 1H, Th-H4); 6.62 (dd, 1H, Fu-H4); 3.72 (s, 3H, CH3) 13C-NMR: (DMSO-ds) d (ppm): 164.0; 154.2; 148.0; 144.1; 136.9, 115.3; 112.7; 108.6; 97.5, 51.3 3-chlorosulfonyl-5- (2-furyl) -2-thiophenecarboxylic acid methyl ester
Zu einer Suspension von 35.42 g (136 mMol) 3-Amino-5(2-furyl)-2-thiophencarbonsäuremethylesterhydro-chlorid in 215 ml conz. Salzsäure werden während \ Stunde bei -12 *C 11.29 g (164 mMol) Natriumnitrit in 16 ml Wasser unter die Flüssigkeitsoberfläche eingebracht und eine Stunde gut gerührt.To a suspension of 35.42 g (136 mmol) of 3-amino-5 (2-furyl) -2-thiophenecarboxylic acid methyl ester hydrochloride in 215 ml of conc. Hydrochloric acid is introduced at -12 * C for 11.29 g (164 mmol) of sodium nitrite in 16 ml of water under the surface of the liquid and stirred well for one hour.
Parallel dazu versetzt man unter Eiskühlung in einem hohen Becherglas 725 ml einer bei 0' C gesättigten Schwefeldioxidlösung in Eisessig (~ 40%ig) mit 47 ml einer bei Raumtemperatur gesättigten wäßrigen Kupfer(ll)chloridlösung. Zu dieser Mischung die Suspension des Diazoniumsalzes aufeinmal zugegeben auf 30 * C erwärmt. Den dadurch verursachten Volumsverlust gleicht man unmittelbar mit 70 ml der Schwefeldioxidlösung aus und rührt insgesamt 2 Stunden bei Raumtemperatur nach.At the same time, 725 ml of a sulfur dioxide solution saturated at 0 ° C. in glacial acetic acid (~ 40%) are mixed with 47 ml of an aqueous copper (II) chloride solution saturated at room temperature while cooling with ice. To this mixture, the suspension of the diazonium salt was added all at once to 30 ° C. The resulting loss of volume is immediately compensated with 70 ml of the sulfur dioxide solution and stirred for a total of 2 hours at room temperature.
Das Reaktionsgemisch wird auf 2 I Eiswasser gegossen, die entstandene Fällung abfiltriert und dreimal mit je 300 ml kaltem Wasser digeriert. Den Feststoff verteilt man zwischen 400 ml Wasser und 300 ml Dichlormethan und extrahiert noch dreimal mit je 200 ml Dichlormethan. Die organische Phase wird über Na2SO*/Aktivkohle getrocknet, filtriert und das Lösungsmittel abgezogen.The reaction mixture is poured onto 2 l of ice water, the precipitate formed is filtered off and digested three times with 300 ml of cold water each time. The solid is distributed between 400 ml of water and 300 ml of dichloromethane and extracted three more times with 200 ml of dichloromethane each. The organic phase is dried over Na2SO * / activated carbon, filtered and the solvent is stripped off.
Ausbeute: 38.46 g braune Kristalle (92% d.Th.) DC: LM..Bz:EhO = 10:1; 0.7 Fp.: 133-136 ”C (Zers) ’H-NMR: (CDCI3) d(ppm): 7.68 (s, 1H, Th-H4); 7.51 (dd, 1H, Fu-H5);6.77 (dd, 1H, Fu-H3); 6.53 (dd, 1H, Fu-H4); 3.99 (s, 3H, CH3) 13C-NMR: (CDCI3) d(ppm): 158.7; 146.1; 144.4; 144.1; 137.5; 131.5; 123.3; 112.5; 109.4; 53.1 5-(2-Furyl)-3-[N-(methoxycarbonylmethyl)-sulfamoyl]-2-thiophencarbonsäure-methylesterYield: 38.46 g of brown crystals (92% of theory) TLC: LM..Bz: EhO = 10: 1; 0.7 mp: 133-136 ”C (dec)’ H NMR: (CDCI3) d (ppm): 7.68 (s, 1H, Th-H4); 7.51 (dd, 1H, Fu-H5); 6.77 (dd, 1H, Fu-H3); 6.53 (dd, 1H, Fu-H4); 3.99 (s, 3H, CH3) 13C-NMR: (CDCI3) d (ppm): 158.7; 146.1; 144.4; 144.1; 137.5; 131.5; 123.3; 112.5; 109.4; 53.1 5- (2-Furyl) -3- [N- (methoxycarbonylmethyl) sulfamoyl] -2-thiophenecarboxylic acid methyl ester
Zu einer Suspension von 30.57 g (99.7 mMol) 3-Chlorsulfonyl-5-(2-furyl)-2-thiophencarbonsäuremethyle-ster und 15.64 g (125 mMol) Glycinmethylesterhydrochlorid in 255 ml absolutem Methanol werden bei 0“C 22.69 g (224 mMol) Triethylamin getropft und eine Stunde gerührt. 6To a suspension of 30.57 g (99.7 mmol) of 3-chlorosulfonyl-5- (2-furyl) -2-thiophenecarboxylic acid methyl ester and 15.64 g (125 mmol) of glycine methyl ester hydrochloride in 255 ml of absolute methanol, 22.69 g (224 mmol ) Triethylamine added dropwise and stirred for one hour. 6
Claims (4)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT253093A AT400437B (en) | 1993-12-14 | 1993-12-14 | Novel N-heterocyclic thienothiazinecarboxamides, process for their preparation and their use |
| EP94119114A EP0658559A1 (en) | 1993-12-14 | 1994-12-05 | Thienothiazin derivatives, process for their preparation and their use as 5-dipoxygenase and cyclooxygenase inhibitors |
| NO944700A NO944700L (en) | 1993-12-14 | 1994-12-06 | New Thienothiazine Derivatives, Process for their Preparation and Pharmaceutical Preparations Containing the Compounds |
| JP6309098A JPH07267964A (en) | 1993-12-14 | 1994-12-13 | Novel N-heterocyclic thienothiazine carboxamide, its production method and its use |
| CN94119307A CN1109059A (en) | 1993-12-14 | 1994-12-13 | Novel thienothiazine derivatives |
| CA002137976A CA2137976A1 (en) | 1993-12-14 | 1994-12-13 | Thienothiazine derivatives |
| US08/355,549 US5679678A (en) | 1991-05-18 | 1994-12-14 | Thienithiazine derivatives |
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| AT253093A AT400437B (en) | 1993-12-14 | 1993-12-14 | Novel N-heterocyclic thienothiazinecarboxamides, process for their preparation and their use |
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| WO2004105766A3 (en) * | 2003-05-27 | 2005-03-03 | Binder Eva Hf | Use of lornoxicam or lornoxicam analogue compounds |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2537070A1 (en) * | 1974-08-26 | 1976-03-18 | Hoffmann La Roche | THIAZINE DERIVATIVES |
| AT352746B (en) * | 1975-08-25 | 1979-10-10 | Hoffmann La Roche | PROCESS FOR PRODUCING NEW THIENOTHIAZIN DERIVATIVES |
| US4180662A (en) * | 1977-09-06 | 1979-12-25 | Hoffmann-La Roche Inc. | Thiazine derivatives |
| ES8604979A1 (en) * | 1985-11-15 | 1986-03-01 | Veris Sl Lab | Carboxamide derivs. of hydroxy methyl thiazine di:oxide |
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1993
- 1993-12-14 AT AT253093A patent/AT400437B/en not_active IP Right Cessation
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2537070A1 (en) * | 1974-08-26 | 1976-03-18 | Hoffmann La Roche | THIAZINE DERIVATIVES |
| AT352746B (en) * | 1975-08-25 | 1979-10-10 | Hoffmann La Roche | PROCESS FOR PRODUCING NEW THIENOTHIAZIN DERIVATIVES |
| US4180662A (en) * | 1977-09-06 | 1979-12-25 | Hoffmann-La Roche Inc. | Thiazine derivatives |
| ES8604979A1 (en) * | 1985-11-15 | 1986-03-01 | Veris Sl Lab | Carboxamide derivs. of hydroxy methyl thiazine di:oxide |
Non-Patent Citations (1)
| Title |
|---|
| CHEM. ABSTR.: BD. 111, NR. 166 771N UND BD. 115, NR. 21532H * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004105766A3 (en) * | 2003-05-27 | 2005-03-03 | Binder Eva Hf | Use of lornoxicam or lornoxicam analogue compounds |
| RU2366425C2 (en) * | 2003-05-27 | 2009-09-10 | БИНДЕР Ева | Application of oxycam compounds |
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